Peter Scholes

CSO, Quotient Sciences

AHPPI Annual Meeting 22nd June 2018

Integrating adaptive pharmaceutical and

clinical strategies to improve flexibility

and efficiency in early development.

What do we mean by “integrating”?

• Dictionary definition:

• “To put together parts or elements and combine them into a whole”

• Early phase studies have historically been performed as separate, stand-alone protocols

• Multi-part programs under a single clinical protocol are now common-place

• Typically, these include single ascending dose, and multiple ascending dose...plus

• Proof of concept or pharmacological effect - biomarkers or PD models in healthy volunteers or patients

• Additional investigations - food interaction, gender/age/ethnic groups, drug-drug interactions, etc

• Are we maximising our potential in early development?

Single ascending

dose

Multiple ascending

dosePOC/POPE

Additional Part

e.g. food effect

Single clinical protocol

What do we mean by “adaptive”

• Dictionary definition:

• “Having an ability to change to suit different conditions”

• Adaptive clinical trials

• “A study that includes a prospectively planned opportunity for modification of one or more specified aspects

of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the

study (FDA guidance)

• “A clinical trial that evaluates a medical device or treatment by observing participant outcomes (and

possibly other measures, such as side-effects) on a prescribed schedule, and modifying parameters of the

trial protocol in accord with those observations” (Wikipedia)

• “An adaptive design is defined as a design that allows modifications to the trial and/or statistical procedures of

the trial after its initiation without undermining its validity and integrity. The purpose is to make clinical trials

more flexible, efficient and fast” (Chow et al 2005)

• Are we maximising our potential in early development?

3

Overview

• Drivers for alternative approaches in early development – don’t forget the drug product

• Introduce Translational Pharmaceutics

• Benefits of integrating GMP manufacturing and clinical testing

• Applications and case studies

• Accelerating FIH to POC

• Reengineering product optimisation

• Personalised manufacturing for patient studies

• Summary

4

Key challenges in todays early development

5

• Attrition remains high through the development life-cycle

• 80% drug candidates have failed by end of Phase II

• Oral bioavailability and tissue exposure is still a key contributor

• Cited as a reason for failure in ~30% of cases

• Physicochemical and biopharmaceutic properties are

challenging

• ~90% NCEs have poor solubility and/or permeability

• Integrated and adaptive clinical protocols alone will not address

these development risks

Getting the product to the patient

6

• Significant time and cost

• Formulations based on animal data

• Clinical testing restricted to pre-defined, pre-manufactured prototypes

Drug substance

Formulation development

Process development

Stability studiesClinical

manufacture & release

Shipping

Clinical packaging &

labelling

ShippingStorage at

Clinic

Dose and study conduct

Reporting

If it’s not right –go back to

start!

Hum

an

Bio

ava

ilabili

ty

Animal Bioavailability

primate

rodents

dog

primate

rodents

dog

Hum

an

Bio

ava

ilabili

ty

Animal Bioavailability

primate

rodents

dog

primate

rodents

dog

Grass and Sinko, DDT Vol.6, No. 12(Suppl.), 2001

Translational Pharmaceutics

The integration of formulation development, real-time adaptive GMP manufacturing and clinical testing

7

Horizontal

integration

Formulation development

Pharmaceutical analysis

Real-time adaptive GMP manufacturing

Translational

Pharmaceutics

Make

Clinical trial

supplies

Pharmaceutical

development

API synthesis

Commercial

manufacture

Test

Patients

Laboratories

Healthy

volunteers

Commercial

development

Clinical Pharmacology Unit

Regulatory affairs

Data analysis & reporting

14 day cycle

Transforming development into “make-test” cycles

8

Day 1-3

• Dose

• Residency

• Safety, PK & PD

Day 4-6

• 72h bioanalysis

Day 7

• PK parameter estimates

Day 8

• Interim decision meeting

• Safety/PK report reviews

• “What next” decision

Day 9-13

• GMP manufacture/release of selected drug product

• Transfer to clinical unit

9

Benefits to industry, regulators and patients

Conventional GMP

practice

Translational

PharmaceuticsImpact

Timeline savings None Typically ≥ 6 months Accelerated POC, expedited formulation optimisation

CMC investment savings None Typically ≥ $500,000 Managed early R&D expenditure

API conservation None Up to 85% reduction Improved efficiency

Flexibility None (fixed compositions) Adaptive within protocol Enhanced decision making

Formulation selection Based on surrogate tools Based on clinical data Increased precision and potential for success

Risk reduction of repeat None Enhanced Reduced exposure of healthy volunteers to NCEs

Knowledge space build Limited High Early application of ICH Q8 QbD principles

Translational Pharmaceutics - key applications

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Maximising the adaptive nature of Phase I studies

11

Accelerating FIH to POC

Early development strategy questions

12

Healthy

volunteer (SAD)

Healthy

volunteer (MAD)Patient (POC)

Question: Is this typically 1 study? Or 2? Or 3?

Potential drug product switching points

Sim

ple

or

En

ab

led

form

ula

tion

s

Solution/Suspension

Solid dosage form

Solution/Suspension Solid dosage form* *

*

Question: How do you develop a suitable drug product for FIH and POC?

?

Researchers encounter stark decisions

• How can we transition from a FIH formulation to a solid oral dosage form without delaying the

pivotal patient studies?

• For every project it is a balance of science, time and cost

Phase IISAD MAD POC

Formulation

strategy

Drug/Powder in bottle/capsuleMinimise investment

until POC

Late switch to solid

delays PhII

Formulated solid dosage formSignificant

investment prior to

FIH

Swift transition to

PhII

D/P in B/CSwitch to solid

between studies via

BA

Phase I duration

extendedSolid dosage form

Real-time manufacture within a FIH program

Additional benefits:

• Manufacture of product as needed, based on emerging clinical data

• No need for bulk manufacture of pre-determined, fixed unit doses

• Conservation of API

• Small batch sizes and only short term stability required

• Precise, fully flexible doses

• Unit dose selected and manufactured based on emerging clinical data

*

• FIH design and objectives unaffected – assessment of

safety, tolerability, PK, PD

• Emerging data reviewed by a SAC to determine dose

progression

• 10 to 14 day interval between cohorts

Drug product selection within a FIH program

• Why include flexible CMC strategies for FIH programs?

• Following rapid FIH entry, switch to a solid oral dosage for POC/Phase II

• Screen formulation technologies e.g. to overcome solubility challenges

Dose 1

Formulation 1

Dose 2

Formulation 1

Dose 3

Formulation 1

Dose 4

Formulation X

Dose 5

Formulation X

Dose 3

Formulation 3

Dose 3

Formulation 2

Selection of Formulation 1, 2 or 3

for progression

Case study:

Managing risk from preclinical PK

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SAD

Dose 1(Dose form 1)

SAD

Dose 2(Dose form 1)

SAD

Dose 3(Dose form 1)

SAD

Dose 4(Selected form)

SAD

Dose 5(Selected form)

SAD

Dose 6(Selected form)

SAD

Dose 3(Dose form 2)

SAD

Dose 3(Dose form 3)

Single clinical protocol

MAD(Selected form)

Drug product

selection

• Differences in bioavailability between solution vrs solid in preclinical species

• Within-study flexibility to test up to 3 formulations

• Single protocol and regulatory submission

• Standard MHRA approval time <20days

• Overall timeline <10mths

• Drug product selected for Phase 2

Case study: FIH formulation assessment & seamless transition to patients

• FIH study performed in healthy volunteers with MEI-401, an oral Pi3k inhibitor

• 3 capsule formulations developed and prioritized for evaluation

• Powder blend; lipid suspension; spray dried dispersion

• Precise unit dose adjustments during SAD

• Blood samples taken to assess target inhibition (basophil activation)

• Drug product suitable for patient trials identified

• Time from initiating CMC activities to patient supply: 12 months

• Positive Phase II data announced at ASCO 2018

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In vitro data generation

and PBPK modelling

Formulation

development

SAD

healthy volunteers

Global product

supply to patients

Translational Pharmaceutics tailored, adaptive, and continuous product supply

Maximising the adaptive nature of Phase I studies

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Re-engineering product optimisation

Sub-optimal PK profiles

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Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Increasing dose

Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Variability Proportionality

Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Half-life

Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Increasing dose

Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Variability Proportionality

Time (Hours)0 24

Time (Hours)0 24

Blo

od

Le

vel o

f D

rug

Half-lifeHalf life Variability Proportionality

• Not to mention………

• Poor exposure

• Positive or negative food effects

Adaptive programs with real-time formulation flexibility

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Clinical dosing

Pharmaceutical

development

program

Regulatory

application

Real time,

adaptive

manufactureClinical

“Make-Test”

cycle

Rapid Formulation development And Clinical Testing

Para

mete

r 1

Parameter 2

Pre-approved

regulatory design space

FP1

FP2

FP3

FP4

>150 programs and >500 formulations

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56%

19%

11%

8%

3% 3%

Modified release

Matrix

Coating

GR

MultiparticulateLipid matrix

30%

22%13%

11%

10%

6%

6%

2%

Solubility

Spray drying

Lipid

Salt form

pH modification

Particle size

Cocrystal

Flow precipitation

Supercritical fluid

44%

34%

8%

7%

3%

2%1% 1%

Applications

Solubility Modified release

Non-oral Route switch

Taste Solid dose development

Combination product Manufacturing process

Case study:

Optimisation of a controlled release product with targeted GI delivery

• Problem Statement:

• LY545694 had demonstrated successful POC

• Short half-life, dose limiting AEs and absorption limited to the small intestine

• Initial controlled release (CR) formulation developed, but resulted in

significant defecation of drug and a subsequent impact on cost of goods

• Target Product Profile:

• Improved CR formulation to deliver all drug within the target region

• Achieve equivalent exposure profile

• Reduce dose and cost of goods

Pharmaceutical Science strategy

• New CR formulation developed with lower viscosity HPMC

• Variable release rate achieved via adjustment in polymer composition

• Reduced dose of 25mg

• Formulations radiolabelled to support scintigraphic imaging

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Regulatory

Application

A B

HPMC K100LV20% w/w 50% w/w

PharmDev

program

GMP

manufacture

Dosing

Scintigraphic Imaging

• Gold standard technique for over 40 years

• Gamma emitting radionuclides used to label the formulation

• Short half-life

• Low radiation doses

• Images are captured using a gamma camera

• Non invasive

• Short imaging times

• Visualise and quantify formulation performance

• Performed in conjunction with PK assessments

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Clinical study design

• Crossover study in 16 healthy volunteers

• 3 formulation prototypes studied

• Provided opportunity to select products in response to emerging data

• Prototype 1 selected to contain 30% Methocel K100LV based upon in-vitro

data

• Data compared to oral solution and Reference CR products

• Interim decisions made based upon:

• Scintigraphic imaging data

• Pharmacokinetic data

25

Prototype 1

Reference CR

Prototype 2

Solution formulation

Unlabelled Reference CR

Prototype 3

14d

14d

14d

Anatomical location of complete erosion

26

0

2

4

6

0

2

4

6

0

2

4

6

0

2

4

6

S PSB DSB AC HF TC SF DC

Nu

mb

er

of

su

bje

cts

Location in GI tract

Reference

CR tablet

Prototype 1

30% HPMC

Prototype 2

24% HPMC

Prototype 3

20% HPMC

MR formulation optimisation - outcomes

• Study decisions driven by an understanding of the drivers impacting on formulation performance

and PK variability

• Efficient delivery of LY545694 to the site of absorption resulted in 30% higher relative

bioavailability

• Prototype 3 was selected for further development

• Timeline to completion <8 months

27

5 wks 8 wks7 wks

FSFD

ReportingClinical

program

Tech Transfer &

CTA preparationRegulatory

Regulatory

submissionDraft CSR

report

8 wks

Lab start

Vol.

screen

2 wks

Maximising the adaptive nature of patient studies

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Re-engineering supply chains

Drug product supply: challenges and solutions

• Typical challenges

• Challenging / sporadic patient recruitment

• Multiple sites / countries

• Patient weight variability requiring dose flexibility

• Formulation stability may be limited

• Small batch size requirements

• Conventional supply chains may not be flexible

to meet these needs

• Real-time adaptive GMP manufacturing offers a

unique solution….

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Case study: real-time adaptive GMP manufacturing and supply

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Proof-of-concept in Alagille Syndrome (ALGS) and Progressive

Familial Intrahepatic Cholestasis (PFIC)

Program requirements/challenges:

• Pediatric patient population

• Solution formulation, limited stability

• Patient packs required for home dosing

• Recruitment sporadic and unpredictable (n=1)

• Patients dosed based upon body weight

• Dose varies during treatment (fixed volume)

• Dose adjustment in response to emerging data

Program design:

• Randomized and blinded design

• On demand, personalized drug product supply

• GMP manufacturing, labelling and packaging

• QP released and shipping

• Supplied up to 124 weeks for daily dosing

• Resupplied every 1-3 months

• >180 patients, >1300 shipments

• >25 sites across 8 countries

Product available for dosing globally within

1-3 weeks of confirmed subject eligibility

Summary

• Integrated and adaptive Phase I protocols are the established norm

• Does this alone adequately address today’s challenges in early drug development?

• Opportunities are presenting from Translational Pharmaceutics

• Integration of GMP manufacturing and clinical testing

• Using clinical data to drive formulation decisions

• Adaptive clinical trials today

• Adaptive protocols and adaptive drug products

• More informed, faster and cost-effective decision making

• Maximised potential for success

• Industry is adopting this approach

• >80% of studies at Quotient benefited from Translational Pharmaceutics (2012-17 data)

31

Assess. Adapt. Accelerate.

peter.scholes@quotientsciences.com